1. Field of the Invention
The present invention pertains to methods of preparing (R)- or (S)-tetrahydrofuranyl ketones. More specifically, the present invention is directed to a method of preparing an industrially applicable (R)- or (S)-tetrahydrofuranyl ketone having high optical purity by dehydration of (R)- or (S)-2-tetrahydrofuran amide in the presence of a dehydrating agent and an amine base, to obtain (R)- or (S)-2-tetrahydrofuran nitrile, after which nucelophilic addition-reaction with a nucleophile and hydrolysis are carried out in order.
2. Description of the Prior Art
Generally, (R)- or (S)-tetrahydrofuranyl ketone compounds are widely employed for preparation of antibiotics which are used as antiviral medicines and of optically active chemicals, and also employed as important medicinal intermediates of optically active medicines and veterinary medicines.
However, most of the conventional techniques are directed to the production of racemic tetrahydrofuranyl ketones, rather than of optically pure (R)- or (S)-tetrahydrofuranyl ketones.
Meanwhile, WO 92/01696 discloses a method for preparation of (R)-2-acetyl-tetrahydrofuran bromide, in which a carboxylic acid moiety in (R)-2-tetrahydrofuroic acid used as a starting material is activated by oxalic acid chloride, and reacted with excessive diazomethane and then further with 48% aqueous hydrogen bromide solution, producing (R)-2-acetyl-tetrahydrofuran bromide. Also, a preparation method of 2-acetyl-tetrahydrofuran chlorides comprising reacting racemic 2-tetrahydrofuroic acid used as a starting material with diazomethane according to the same manner as in the above patent and further with hydrochloric acid, is described in J. Antibiot. 1994, 47(2), 253. But, the above methods cannot be applied on an industrial scale due to use of diazomethane being highly explosive.
In J. Heterocycl. Chem. 1995, 32(1), 109, a preparation method of tetrahydrofuranyl ketone is disclosed by reaction of racemic 2-tetrahydrofuroic acid and phenylmagnesium bromide or phenyllithium. However, this method is disadvantageous since even though (R)- or (S)-2-tetrahydrofuroic acid is employed as a starting material, the optical purity of the resultant tetrahydrofuranyl ketone is lowered due to racemization in the application on the industrial scale. Additionally, tertiary alcohols are produced in large amounts as by-products, thus making it difficult to apply the above method to production on the large scale.
Further, it is well known in the art that since ketones, resulting from a nucleophilic addition reaction of carboxylic acids, have higher activity for the nucleophilic addition than carboxylic acids used as a starting material, tertiary alcohols are produced in large amounts through additional nucleophilic addition reaction of said ketones, thus decreasing a reaction yield. Hence, diverse attempts have been conducted to overcome such problems.
For example, it is known that carboxylic acid and lithium hydride are reacted at a molar ratio of 1:1, to produce lithium carboxylate, which is then reacted with an organic lithium compound or a Grignard reagent, to prepare ketone. But, when this method is applied to preparation of an optically pure tetrahydrofuranyl ketone on an industrial scale, racemization occurs. So, the resultant ketone is low in optical purity.
Under these circumstances, there is proposed a preparation method in which carboxylic acid is converted, by use of N,O-dimethylhydroxyamine hydrochloride, to N,O-dimethyl hydroxiamide, followed by reacting with an organic lithium compound or a Grignard reagent to yield ketone. This method is advantageous in terms of suppression of tertiary alcohols produced as a by-product, but is disadvantageous due to use of expensive N,O-dimethylhydroxyamine hydrochloride. Therefore, it is difficult to industrially apply such a method, in terms of economic benefit. In particular, when this method is used for preparation of an optically pure tetrahydrofuranyl ketone on an industrial scale, racemization occurs, thus the produced ketone has low optical purity.
According to Tetrahedron Lett. 1984, 25(42), 4805, a method of preparing ketone is proposed, in which carboxylic acid is activated with thionyl chloride and reacted with a Grignard reagent in the presence of iron (III) catalyst to produce ketone. But, when such a method is also applied to preparation of an optically pure tetrahydrofuranyl ketone on an industrial scale, racemization is so unavoidable that the resultant ketone is low in optical purity.